The objective of the proposed research is to study metabolic abnormalities in rheumatoid arthritis, including the hypothesis that hypohistidinemia participates in the pathogenesis of the disease. The approach is based on three findings: (1) The serum histidine concentration is decreased specifically in patients with rheumatoid arthritis. (2) Administration of oral L-histidine to patients with rheumatoid arthritis in a single-blind and double-blind trial was associated with statistically significant clinical and laboratory (hematocrit, serum salicylate, titer of rheumatoid factor) improvement. (3) L-histidine, gold thiomalate, and penicillamine inhibit - and hyaluronic acid augments - the thermal aggregation of human gamma globulin. The methods to be used are the following: (1) Oral L- histidine will be further evaluated by both single-blind and double-blind analysis for its effect on rheumatoid arthritis. Emphasis will be on the effect of histidine on the anemia of the disease, on the concentration of rheumatoid factor, and on rheumatoid arthritis in children. Patient characteristics (e.g. a high ESR) most likely to predict a response to oral L-histidine will be sought. (2) The chemical mechanisms by which thermal and mechanical aggregation of human gamma globulin take place will be studied further. Dithiobisnitrobenzoic acid will be used to seek direct evidence for the liberation of free SH groups during copper-catalyzed thermal and copper-independent mechanical aggregation of human gamma globulin and to study the effect of hyaluronate on thermally and mechanically-induced disulfide fission. (3) A rapid simple fluorescence method for measuring the concentration of histidine in serum will be used in patients with a wide variety of conditions in order to further confirm and delineate the apparent specificity of hypohistidinemia for rheumatoid arthritis.